Ser/Thr Protein Phosphatase Type 5 (PP5) Is a Negative Regulator of Glucocorticoid Receptor-Mediated Growth Arrest

Zuo, Zhuang; Urban, Gudrun; Scammell, Jonathan G.; Dean, Nicholas M.; McLean, Tammy K.; Aragon, Ileana; Honkanen, Richard E.

doi:10.1021/bi990842e

Cited by 119 publications

(142 citation statements)

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“…To gain insight into which of the cantharidin-sensitive PPases affect cell cycle progression and survival, we developed siRNA and antisense oligonucleotides capable of suppressing the expression of PP1g1 (20), PP5 (24,28,30), and, here, PP2Aa and PP2Ah. FACS analysis of propidium iodide -stained A549 cells treated with siRNA or antisense oligonucleotides targeting each of these PPase individually revealed that the suppression of PP5 expression results in a G 1 growth arrest with the concomitant increase in the expression of p21 Waf1/cip1 (24).…”

Section: Discussionmentioning

confidence: 99%

Cantharidin-induced mitotic arrest is associated with the formation of aberrant mitotic spindles and lagging chromosomes resulting, in part, from the suppression of PP2Aα

Bonness

Aragon

Rutland³

et al. 2006

Molecular Cancer Therapeutics

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Cantharidin, a natural vesicant, inhibits the activity of several PPP family phosphatases, displays antitumor activity, and induces apoptosis in many types of tumor cells. However, the molecular mechanisms underlying the antitumor activity of cantharidin are not clear. Here, doseresponse studies confirm a strong correlation between the suppression of phosphatase activity and cell death. Flow cytometry analysis indicates that before apoptosis, cantharidin delays cell cycle progression following DNA replication with no apparent effect on G 1 -S or S-G 2 phase progression. In contrast, studies with double thymidinesynchronized populations of cells indicate that cantharidin can rapidly arrest growth when added during G 2 or early M phase. Immunostaining indicates that cell cycle arrest occurs before the completion of mitosis and is associated with the appearance of aberrant mitotic spindles. Live cell imaging with time-lapse microscopy shows that cantharidin disrupts the metaphase alignment of chromosomes and produces a prolonged mitotic arrest, with the onset of apoptosis occurring before the onset of anaphase. To explore the contribution of individual phosphatases, antisense oligonucleotides and small interfering RNA were developed to suppress the expression of cantharidinsensitive phosphatases. The suppression of PP2AA, but not PP2AB, is sufficient to induce metaphase arrest, during which time lagging chromosomes are observed moving between the spindle poles and the metaphase plate. Immunostaining revealed slightly abnormal, yet predominately bipolar, mitotic spindles. Nonetheless, after a 10-to 15-hour delay, the cells enter anaphase, suggesting that an additional cantharidin-sensitive phosphatase is involved in the progression from metaphase into anaphase or to prevent the onset of apoptosis in cells arrested during mitosis.

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Section: Discussionmentioning

confidence: 99%

Cantharidin-induced mitotic arrest is associated with the formation of aberrant mitotic spindles and lagging chromosomes resulting, in part, from the suppression of PP2Aα

Bonness

Aragon

Rutland³

et al. 2006

Molecular Cancer Therapeutics

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“…ISIS 15534 treatment also markedly increases the association of GR with its cognate DNA binding sequence and induces GR-transcriptional activity in the absence of glucocorticoids (18). When combined, ISIS 15534 and dexamethasone, a potent GR agonist, have an additive effect, with dexamethasone-mediated induction of GR reporter plasmid activity elevated to a level that is ϳ10 times greater than the maximal response obtainable in the presence of PP5 (18).Treatment with ISIS 15534 also suppresses the growth of some, but not all, human tumor cells (9,15,18). In p53 wildtype lung carcinoma cells, treatment with ISIS 15534 produces G 1 growth arrest, which occurs with a concomitant increase in the expression of the cyclin-dependent protein kinases inhibitor protein, p21 Waf1/Cip1 (15,18).…”

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“…Treatment with ISIS 15534 also suppresses the growth of some, but not all, human tumor cells (9,15,18). In p53 wildtype lung carcinoma cells, treatment with ISIS 15534 produces G 1 growth arrest, which occurs with a concomitant increase in the expression of the cyclin-dependent protein kinases inhibitor protein, p21 Waf1/Cip1 (15,18).…”

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“…In p53 wildtype lung carcinoma cells, treatment with ISIS 15534 produces G 1 growth arrest, which occurs with a concomitant increase in the expression of the cyclin-dependent protein kinases inhibitor protein, p21 Waf1/Cip1 (15,18). In contrast, in p53 Ϫ/Ϫ human fibroblast or p53-defective T-24 bladder carcinoma cells, ISIS 15534 treatment does not suppress growth or induce the expression of p21 Waf1/Cip1 (18).…”

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“…In GR-responsive A549 cells, treatment with ISIS 15534, a potent and specific suppresser of PP5 expression (9,15,16), induces the nuclear accumulation of GRs (17). ISIS 15534 treatment also markedly increases the association of GR with its cognate DNA binding sequence and induces GR-transcriptional activity in the absence of glucocorticoids (18). When combined, ISIS 15534 and dexamethasone, a potent GR agonist, have an additive effect, with dexamethasone-mediated induction of GR reporter plasmid activity elevated to a level that is ϳ10 times greater than the maximal response obtainable in the presence of PP5 (18).…”

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Identification of a Functional Link for the p53 Tumor Suppressor Protein in Dexamethasone-induced Growth Suppression

Urban

Golden

Aragon

et al. 2003

Journal of Biological Chemistry

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Serine/threonine phosphatase 5 (PP5) can act as a suppresser of p53-dependent growth suppression and has been reported to associate with several proteins, including the glucocorticoid receptor/heat-shock protein-90 complex. Still, the physiological/pathological roles of PP5 are unclear. To characterize the relationship of PP5, glucocorticoid receptor activation and p53, here we describe the development of chimeric antisense oligonucleotides that potently inhibit human p53 expression. This allowed us to regulate the expression of either p53 (e.g. with ISIS 110332) or PP5 (e.g. with ISIS 15534) in genetically identical cells. Studies with ISIS 110332 revealed that the suppression of p53 expression is associated with a decrease in the basal expression of the cyclin-dependent kinase inhibitor protein, p21 WAF1/Cip1 , and a concomitant increase in the rate of cell proliferation. Suppression of p53 also blocks dexamethasone-induced p21 WAF1/Cip1 expression and G 1 -growth arrest. Furthermore, treatment with ISIS 110332, but not the mismatched controls, ablates the suppression of growth produced by prior treatment with dexamethasone. Additional studies revealed that dexamethasone-dependent p21 WAF1/Cip1 expression occurs without an apparent change in p53 protein levels or the phosphorylation status of p53 at Ser-6, -37, or -392. However, dexamethasone treatment is associated with an increase in p53 phosphorylation at Ser-15. Suppression of PP5 expression with ISIS 15534 also results in the hyperphosphorylation of p53 at Ser-15. Together, these findings indicate that the basal expression of p53 plays a functional role in a glucocorticoid receptor-mediated response regulating the expression of p21 Waf1/Cip1 via a mechanism that is suppressed by PP5 and associated with the phosphorylation of p53 at Ser-15.Serine/threonine phosphatase 5 (PP5) is an okadaic acid/ calyculin A-sensitive phosphatase that is expressed ubiquitously in mammals and has been reported to associate with the atrial natriuretic peptide receptor (1), the heat shock protein 90 (Hsp-90) 1 -glucocorticoid receptor (GR) heterocomplex (2, 3), the CDC16/CDC27 subunits of the anaphase-promoting complex (4), cryptochrome 2 (5), apoptosis signal-regulating kinase1 (6), Hsp90-dependent heme-regulated eIF2␣ kinase (7), and the G␣ 12 /G␣ 13 subunits of heterotrimeric G proteins (8). In estrogen-responsive breast carcinoma cells, the expression of PP5 is induced by treatment with estrogen, and the constitutive expression of PP5 converts MCF-7 cells into an estrogen-independent phenotype (9). Still, determining the physiological/pathological roles of PP5 has proven difficult for many reasons. First, in a crude cell homogenate PP5 exists predominately in an inactive state (for review see Ref. 10). Second, the physiological activators of PP5 are unknown. Third, when activated by the addition of polyunsaturated lipids or protease mediated cleavage of the N-terminal autoinhibitory domain (11, 12), the activity of PP5 cannot be distinguished from that of PP2A and PP1, whi...

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Molecular Mechanisms of Glucocorticoid Receptor Action

Bhavsar

Adcock

2008

Overcoming Steroid Insensitivity in Respiratory Disease

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Ser/Thr Protein Phosphatase Type 5 (PP5) Is a Negative Regulator of Glucocorticoid Receptor-Mediated Growth Arrest

Cited by 119 publications

References 53 publications

Cantharidin-induced mitotic arrest is associated with the formation of aberrant mitotic spindles and lagging chromosomes resulting, in part, from the suppression of PP2Aα

Cantharidin-induced mitotic arrest is associated with the formation of aberrant mitotic spindles and lagging chromosomes resulting, in part, from the suppression of PP2Aα

Identification of a Functional Link for the p53 Tumor Suppressor Protein in Dexamethasone-induced Growth Suppression

Molecular Mechanisms of Glucocorticoid Receptor Action

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